1,2,3,4-tetrahydrocarbazole-2-carboxylic acids and their derivatives

ABSTRACT

1,2,3,4-Tetrahydrocarbazoles and cyclopenta(b)indoles prepared from the corresponding phenyl hydrazines and corresponding cyclohexanones or cyclopentanones, respectively, are described. The products of the invention are useful anti-inflammatory, analgesic and anti-rheumatic agents.

ite States Patent Berger et a1.

1,2,3,4-TETRAHYDROCARBAZOLE-Z- CARBOXYLIC ACIDS AND THEIR DERIVATIVES Inventors: Leo Berger, Montclair; Alfred John Corraz, Wayne, both of NJ.

Assignee: Hoffmann-La Roche Inc., Nutley,

Filed: Jan. 22, 1973 Appl. No.: 325,764

Related U.S. Application Data Continuation of Ser. No. 133,738, April 15, 1971,

abandoned, which is a continuation-in-part of Ser. No. 40,443, May 25, 1970, abandoned.

U.S. Cl 260/315, 260/326.27, 260/326.29, 260/326.5 S, 260/326.5 SF, 260/326.5 B, 260/326.62, 260/397.7 R, 260/569, 260/464, 260/468 K, 260/514 K, 260/586 R, 424/274 Int. Cl C07d 27/68 Field of Search 260/315 References Cited UNITED STATES PATENTS 10/1970 Yamamto et a1. 260/315 OTHER PUBLICATIONS J. Heterocyclic Chemistry 7: 239-241 (Feb. 1970) Allen Primary Examiner-Henry R. Jiles Assistant Examiner-S. D. Winters Attorney, Agent, or Firm-Samuel L. Welt; Bernard S. Leon; William G. Isgro [57] ABSTRACT 1,2,3,4-Tetrahydrocarbazoles and cyclopenta[b]indoles prepared from the corresponding phenyl hydrazines and corresponding cyclohexanones or cyclopentanones, respectively, are described. The products of the invention are useful anti-inflammatory, analgesic and anti-rheumatic agents.

15 Claims, No Drawings 1 l,2,3,4-TETRAI-IYDROCARBAZOLE-Z- CARBOXYLIC ACIDS AND THEIR DERIVATIVES CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of US. Pat. application Ser. No. 133,738, filed Apr. 15, 1971, now abandoned which in turn is a continuation-in-part of US. Pat. application Ser. No. 40,443, filed May 25, 1970, now abandoned.

BRIEF SUMMARY OF THE INVENTION The invention relates to compounds of the formula (CII2)n on A. (l

wherein A is cyano, hydroxy or lower alkoxy, Y is hydrogen or methyl, and m is O to 7, or

wherein B is hydroxy, carboxy, lower alkyl, lower alkoxy, amino, mono-lower alkylamino, di-lower alkylamino, amino-lower alkoxy, mono-lower alkyl-amino-lower alkoxy, di-lower alkylamino-lower alkoxy, Y is hydrogen or methyl and p is to 7, provided that when n is 2 and R is COOH, at least one of R, or R must be other than hydrogen, and provided that when R is acyl or halo-substituted acyl, R, must be other than hydrogen or lower alkoxy, their enantiomers, and when R, is carboxy and/or when B is hydroxy or carboxy, salts thereof with pharmaceutically acceptable bases, and when R, is amino, monolower alkylamino or di-lower alkylamino, and/or when B is amino-lower alkoxy, mono-lower alkylamino-lower alkoxy or di-lower alkylamino-lower alkoxy, addition salts thereof with pharmaceutically acceptable acids.

The end products are useful as anti-inflammatory, analgesic and anti-rheumatic agents.

DETAILED DESCRIPTION OF THE INVENTION As used herein, the term lower alkyl denotes a straight or branched chain hydrocarbon group containing l-7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, neopentyl, pentyl, heptyl, and the like. The term lower alkoxy denotes an alkyl ether group in which the alkyl group is as described above, for example, methoxy, ethoxy,

propoxy, isopropoxy, butoxy, pentoxy and the like. The term halogen denotes all the halogens; that is, bromine, chlorine, fluorine and iodine; bromine and chlorine are preferred. The term aryldenotes phenyl or phenyl bearing one or more substituents selected from the group consisting of halogen, trifluoromethyl, lower alkyl, lower alkoxy, nitro, amino, lower alkylamino and di-lower alkylamino. The term aralkyl as used herein denotes a straight or branched chain lower alkyl group in which one or more of the hydrogen atoms have been replaced by an aryl group. The term acyl denotes an alkanoyl" group derived from an aliphatic carboxylic acid of 1 to 7 carbon atoms, for example, formyl, acetyl, propionyl, and the like, and an aroyl group derived from an aromatic carboxylic acid, such as benzoyl and the like. The term lower alkylenedioxy preferably denotes methylenedioxy and the like.

Exemplary of mono-lower alkylamino are methylamino, ethylamino and the like. Exemplary of dilower alkylamino are dimethylamino, diethylamino and the like. Exemplary of amino-lower alkoxy arev aminomethoxy, aminoethoxy and the like. Exemplary of mono-lower alkylamino-lower alkoxy are methylaminomethoxy, ethylaminoethoxy and the like. Exemplary of di-lower alkylamino-lower alkoxy are dimethylaminomethoxy, diethylaminoethoxy and the like. Exemplary of di-lower alkylsufamoyl are dimethylsufamoyl, diethylsulfamoyl and the like.

The invention relates to compounds of the formula l R: I

wherein n and r are independently l or 2; is hydrogen, halogen, hydroxy, cyano, lower alkyl, lower alkoxy, benzyloxy, lower alkylthio, trifluoromethyl, carboxy, carbo-lower alkoxy, nitro, amino, monolower alkylamino, di-lower alkylamino, sulfamoyl, di-lower alkylsulfamoyl or difluoromethylsulfonyl, and when r is 2, R, with an adjacent R, is also lower alkylenedioxy; R is hydrogen, lower alkyl, acyl, halo-substituted acyl, aralkyl or halo-aralkyl; R is 0111) -A, Y m

wherein A is cyano, hydroxy or lower alkoxy, Y is hydrogen or methyl, and m is 0 to 7, or

CH i13, U1.

wherein B is hydroxy, carboxy, lower alkyl, lower alkoxy, amino, monolower alkylamino, di-lower alkylamino, amino-lower alkoxy, mono-lower alkylamino-lower alkoxy, or di-lower alkylaminolower alkoxy, Y is hydrogen or methyl and p is 0 to 7, provided that when n is 2 and R is CO0H, at least one of R, or R must be other than hydrogen, and provided that when R is acyl or haloin I wherein R R R and n are as previously described, their enantiomers, and the respective salts thereof as herein described. Preferred compounds of formula I wherein n is l have the formula wherein R, is halogen, lower alkyl or lower alkoxy; R is hydrogen and R is carboxy, their enantiomers, and salts thereof with pharmaceutically acceptable bases.

Preferred compounds of formula I wherein n is 2 have the formula wherein R is halogen, lower alkyl or lower alkoxy;

R' is hydrogen and R' is carboxy, their cnantiomcrs, and salts thereof with pharmaceuti cally acceptable bases.

Preferred compounds of formula la are 7-chlorocyclopenta [blindole-Z-carboxylic acid, 7- methylcyclopenta[b]indole-2-carboxylic acid and 7- methoxy-cyclopenta[b]indole-2-carboxylic acid.

Preferred compounds of formula lb are 6-chlorol,2,3,4-tetrahydrocarbazole-2-carboxylic acid, 6- methyl-1,2,3 ,4-tetrahydrocarbazole-2-carboxylic acid and 6-methoxy-1,2,3,4-tetrahydrocarbazole-2- carboxylic acid.

Examples of compounds of this invention corresponding to formula I wherein n is 2 are:

6-chloro-l ,2,3,4-tetrahydrocarbazole-Z-carboxylic acid;

6-chloro-l ,2,3 ,4-tetrahydrocarbazole-2-carboxylic acid ethyl ester;

-methyl-l ,2,3,4-tetrahydrocarbazole-Z-carboxylic acid;

6-methoxyl ,2,3 ,4-tetrahydrocarbazole-Z-carboxylic acid;

9-(4-chlorobenzyl)-6-methoxyl ,2,3,4-tetrahydrocarbazole-Z-carboxylic acid;

6-nitro-l ,2,3 ,4-tetrahydrocarbazole-2-carboxylic acid;

7-chloro-l ,2,3 ,4-tetrahydrocarbazole-2-carboxylic acid;

7-methyl-1,2,3 ,4-tetrahydrocarbazole-2-carboxylic acid;

8-chloro-l ,2,3,4-tetrahydrocarbazole-Z-carboxylic acid;

6-fluoro-1,2,3,4-tetrahydrocarbazole-2-carboxylic acid;

6-bromo-l ,2,3,4-tetrahydrocarbazole-2-carboxylic acid;

6,7-dichloro-l ,2,3,4-tetrahydrocarbazole-2- carboxylic acid;

5 ,6-dichloro-1 ,2,3 ,4-tetrahydrocarbazole-2- carboxylic acid;

-trifluoromethyll ,2,3 ,4-tetrahydrocarbazole-Z- carboxylic acid;

6-chloro-7-methyll ,2,3,4-tetrahydrocarbazole-2- carboxylic acid;

6-chloro-5-methyl-1,2,3 ,4-tetrahydrocarbazole-2- carboxylic acid;

9-methyl-l ,2,3 ,4-tetrahydrocarbazole-2-carboxylic acid;

7,8-dichloro-l ,2,3,4-tetrahydrocarbazole-2- carboxylic acid;

1,2,3 ,4-tetrahydro-6-sulfamoylcarbazole-2- carboxylic acid;

6-difluoromethylsulfonyl- 1 ,2,3,4-

tetrahydrocarbazole-2-carboxylic acid;

6-carbethoxyl ,2,3 ,4-tetrahydrocarbazole-Z- carboxylic acid;

5-chloro-l ,2,3,4-tetrahydro-6-sulfamylcarbazole-2- carboxylic acid;

6-chloro-9-(p-chlorobenzoyl)-l,2,3,4-

tetrahydrocarbazole-2-carboxylic acid ethyl ester;

9-benzoyl-6-chlorol ,2,3 ,4-tetrahydrocarbazole-2- carboxylic acid;

6-dimethylsulfamoyll ,2,3 ,4-tetrahydrocarbazole-2- carboxylic acid;

6-methylthio-l ,2,3,4-tetrahydrocarbazole-2- carboxylic acid;

o-benzyloxyl ,2,3 ,4-tetrahydrocarbazole-2- carboxylic acid;

6-cyanol ,2,3 ,4-tetrahydrocarbazole-Z-carboxylic acid;

6-carboxy-l ,2,3 ,4-tetrahydrocarbazole-Z-carboxylic acid;

6-ethyl-1,2,3 ,4-tetrahydrocarbazole-Z-carboxylic acid;

6,7-methylenedioxy-l ,2,3,4-tetrahydrocarbazole-2- carboxylic acid;

6-acetyl-l ,2,3 ,4-tetrahydrocarbazole-2-carboxylic acid,

6-iodol ,2,3 ,4-tetranhydrocarbazole-2-carboxylic acid;

6-chloro-l ,2,3,4-tetrahydrocarbazole-2-carboxylic acid dimethylaminoethyl ester;

6,9-dimethyl-1,2,3,4-tetrahydrocarbazole-2- carboxylic acid;

6-chloro-l ,2,3,4-tetrahydrocarbazole-2-carboxylic acid dimethylaminoethyl ester hydrochloride;

6-chloro-N,N-dimethyl-1,2,3 ,4-tetrahydrocarbazole- 2-carboxamide;

6-methyll ,2,3 ,4-tetrahydrocarbazole-2-carboxylic acid ethyl ester;

6-hydroxyl ,2,3 ,4-tetrahydrocarbazole-2-carboxylic acid; and the like.

Seliiiiie I wherein R,, R and r are as previously described, and

wherein A is cyano, hydroxy or lower alkoxy, Y is hydrogen or methyl, and m is 0-7, or

wherein B is hydroxy, carboxy, lower alkyl, lower alkoxy. amino, mono-lower alkylamino or di-lower alkylamino. Y is hydrogen or methyl, and p is O7.

ln Reaction Scheme l, the reaction of the hydrazine of formula II with the cyalopentanone of formula III to yield the cyclopenta[b]indoles of formula la is carried out at a temperature in the range of about room temperature to about the reflux temperature of the reaction mixture; preferably, it is carried out at the reflux temperature of the reaction mixture. The reaction is effected in the presence of a solvent, for example, water, a lower alkanol such as methanol, ethanol or the like, acetic acid, formic acid, hexane, dioxane, benzene, toluene, dimethylformamide and the like, and an acidic condensing agent as used in the Fischer Indole synthesis, for example, hydrochloric acid, sulfuric acid, phosphoric acid, zinc chloride, copper chloride, boron trifluoride and the like, and various combinations thereof. Alternatively, the reaction of the hydrazine of formula II with the cyclopentanone of formula III can be effected by thermal cyclization with or without solvent. Conveniently, such cyclization is effected at an elevated temperature, for example, at a temperature in the range of from about C. to about 200C.

The separation of the desired cyclopenta[b]indole of formula Ia can be effected utilizing known techniques, for example, filtration, crystallization, distillation and the like.

The acids of formula Ia, i.e., the compounds of formula Ia, wherein B is hydroxy, and salts of such acids with bases, can be converted to a compound of formula I wherein B is amino-lower alkoxy, mono-lower alkylamino-Iower alkoxy or di-lower alkylamino-lower alkoxy by known procedures. For example, a salt of an acid of formula I is reacted with an amino-lower alkyl halide, mono-lower alkylamino-lower alkyl halide or di-lower alkylamino-lower alkyl halide, exemplary of which are aminoethyl chloride, methylamino-ethyl bromide, diethylaminomethyl chloride and the like, to yield the desired end product. The temperature at which the reaction is effected is not critical;'conveniently, the reaction is carried out at a temperature in the range of from about room temperature and about the reflux temperature of the reaction mixture. Conveniently, the reaction can be carried out in a polar solvent, such as dimethylformamide, dimethylsulfoxide or the like. The molar ratio of reactants is not critical. Preferably, the reactants are utilized in a 1:1 molar ratio.

Preparation of compounds of formula I wherein n is 2 is exemplified by Reaction Scheme II:

Scheme M Fischer (Rm NH I a I 2 n 0e N 0 R3 R2 IV RJI wherein R R and r are as previously described, and

R3 (III A,

wherein A is cyano, hydroxy or lower alkoxy, Y is hydrogen or methyl, and m is 0-7, or

wherein B is hydroxy, carboxy, lower alkyl, lower alkoxy, amino, mono-lower alkylamino or di-lower alkylamino, Y is hydrogen or methyl, and p is O7.

In Reaction Scheme II, the reaction of the hydrazine of formula II with the cyclohexanone of formula IV to yield the corresponding 1,2,3,4-tetrahydrocarbazoles of formula Ib is carried out at a temperature in the range of from about room temperature to about the reflux temperature of the reaction mixture; preferably, it is carried out at the reflux temperature of the reaction mixture. The reaction is effected in the presence of a solvent, for example, water, a lower alkanol, such as methanol, ethanol or the like, acetic acid, formic acid, hexane, dioxane, benzene, toluene, dimethylformamide and the like, and an acidic condensing agent as used in the Fischer Indole synthesis, for example, hydrochloric acid, sulfuric acid, phosphoric acid, zinc chloride, copper chloride, boron trifluoride and the like, and various combinations thereof. Alternatively, the reaction of the hydrazine of formula II with the cyclo hexanone of formula IV can be effected by thermal cyclization with or without solvent. Conveniently, such cyclization is effected at an elevated temperature, for example, at a temperature in the range of from about 80C. to about 200C.

The separation of the desired l,2,3,4- tetrahydrocarbazole of formula lb can be effected utilizing known techniques, for example, filtration, cyclization, distillation and the like.

The acids of formula lh, i.c., the compounds of formula lb, wherein B is hydroxy, and salts of such acids with bases, can be converted to a compound of formula I wherein B is amino-lower alkoxy mono-lower alkylamino-lower alkoxy or di-lower alkylaminolower alkoxy by known procedures. For example, a salt of an acid of formula I is reacted with an amino-lower alkyl halide, mono-lower alkylamino-lower alkyl halide or di-lower alkylamino-lower alkyl halide, exemplary of which are aminoethyl chloride, methylamino-ethyl bromide, diethylaminomethyl chloride and the like, to yield the desired end product. The temperature at which the reaction is effected is not critical; conveniently, the reaction is carried out at a temperature in the range of from about room temperature and about the reflux temperature of the reaction mixture. Conveniently, the reaction can be carried out in a polar solvent, such as dimethylformamide, dimethylsulfoxide or the like. The molar ratio of reactants is not critical. Preferably, the reactants are utilized in a 1:1 molar rano.

Exemplary of the compounds of formula II, utilized as reactants in the process of the invention, are:

p-chlorophenylhydrazine;

m-chlorophenylhydrazine;

o-chlorophenylhydrazine;

p-fluorophenylhydrazine;

p-bromophenylhydrazine;

3,4-dichlorophenylhydrazine;

p-trifluoromethylphenylhydrazine;

N-chloro-3-methylphenylhydrazine;

2,3-dichlorophenylhydrazine;

p-methylphenylhydrazine; m-methylphenylhydrazine; p-methoxyphenylhydrazine;

N -(4-chlorobenzyl)-p-chlorophenylhydrazine;

p-nitrophenylhydrazine;

l-methyl-l-phenylhydrazine; p-sulfonamidophenylhydrazine; p-(difluoromethylsulfonyl)-phenylhydrazine; p-carbethoxyphenylhydrazine; and 4-aminosulfonyl-3-chlorophenylhydrazine.

. Exemplary ot the compounds of formula III, utilized as reactants in the process of the invention, are:

cyclohcxanoncJ-carhoxylic acid;

cyclohexanone-3-acetic acid; and

cyclohexanone-3-carboxylic acid ethyl ester.

Exemplary of the compounds of formula IV, utilized as reactants in the process of the invention, are:

cyclopentanone-3-carboxylic acid;

cyclopentanone-3-acetic acid; and cyclopentanone-3-carboxylic acid ethyl ester.

The compounds of formula I when R is amino, mono-lower alkylamino, di-lower alkylamino, and/or when B is amino-lower alkoxy, amino-lower alkylamino-lower alkoxy or di-lower alkylamino-lower alkoxy, form addition salts with pharmaceutically acceptable organic or inorganic acids such as hydrohalides, e.g., hydrochloride, hydrobromide, hydroiodide, other mineral acid salts such as sulfate, nitrate, phosphate and the like, alkyland mono-arylsulfonates such as ethanesulfonate, toluenesulfonate, benzenesulfonate, or the like, other organic acid salts such as acetate,

tartrate, maleate, citrate, benzoate, salicylate, ascorbate and the like.

The compounds of formula l, when R is carboxy and/or B is hydroxy or carboxy, form salts with pharmaceutically acceptable bases. Exemplary of such bases are alkali metal hydroxides, such as sodium hydroxide, potassium hydroxide, and the like; alkaline earth hydroxides, such as calcium hydroxide, barium hydroxide and the like; sodium alkoxides, such as sodium etholate, potassium etholate and the like; organic bases such as piperidine, diethanolamine, N- methylglucamine, and the like. Also included are the aluminum salts of the compounds of formula I, as above.

The compounds of formula 1, including the salts of those compounds of formula I which form salts with pharmaceutically acceptable bases and acids, possess anti-inflammatory, analgesic and anti-rheumatic activity, and are therefore useful as antiinflammatory, analgesic and anti-rheumatic agents. Their pharmacologically useful activities are demonstrated in warmblooded animals using standard procedures.

For example, the anti-inflammatory activity is demonstrated in Albino rats of Hart Strain, weighing 125-155 gms. The test animals are given 10 mls. of vehicle, which contains the test compound per kg. of body weight. The animals are treated daily for 5 consecutive days. Three hours after the first treatment, 0.05 ml. of an 0.5 percent suspension of heat killed dessiccated Mycobacterium butyricum in U.S.P. olive oil, which has been steam sterilized for 30 minutes, is injected into the right hind foot of each rat. The paw volume is measured immediately after the injection of the adjuvant and again 96 hours later. The difference is recorded as volume as edema. The paw volume is measured by immersion of the paw into a column of mercury to an ink mark exactly at the level of the lateral malleolus. Percent inhibition is calculated by dividing the average control edema minus the average treatment edema by the average control edema times 100. The percent inhibition is plotted against dose on semilogarithmic probability paper and the dose required to produce a 30 percent reduction in edema is estimated therefrom and is expressed as ED Hilgar, A. G. and Hummel, D. J.: Endocrine Bioassay Date. No. l, p. 15, August I964 (Cancer Chemotherapy National Service Center,

N.l.H.)

When 6-chloro-l ,2,3,4-tetrahydrocarbazole-2 carboxylic acid, which has demonstrated an LD of, for example, I mg. p.o. in mice, is utilized as the test substance at a dosage of mg. p.o., an antiinflammatory activity is observed (ED 10).

The antipyretic activity of the compounds of the invention is demonstrated, for example, utilizing 30 male rats divided into six groups containing 5 rats/group. Control animals are given 1 cc/lOO g. body weight of the vehicle. The test drug animals are given 200 mg/kg. of the drug in a concentration of 2 percent. Soluble and insoluble compounds are administered orally in aqueous suspended vehicle. One hour after administration of drug, these rats are injected with 0.1 ml. of a 2 percent suspension of Brewers yeast beneath the plantar surface of the foot. Two hours after drug injections and 1 hour after the irritant, the temperatures of the infiammed foot, the normal foot and the rectum are recorded with the help of a thermocouple. Results are reported as degrees change from controls. The temperatures are averaged for the inflammed foot, the normal foot and the rectum. The averages for the treated groups are compared with the control averages and the results noted as degrees change from control.

When o-chloro-l ,2 ,3 ,4-tetrahydrocarbazole-2- carboxylic acid, which has demonstrated an LD of, for example, 1120 mg. p.o. in mice, is utilized as the test substance at a dose of 200 mg/kg., an antipyretic activity is observed.

The analgesic activity of the compounds of the invention is demonstrated, for example, employing the method which is a modification of that described by Eddy (1950), Wolfe and MacDonald (1944) and Eddy and Leimbach (1952). The method determines the reaction time of mice dropped onto a hot plate maintained at 55 iO.5C. Six groups of male mice (5 mice/- group) weighing between -30 grams are utilized. The initial reaction time of these mice is determined once, and the reaction time of each group is then averaged. The mice are then administered the vehicle and- /or the compound to be tested by the oral, intraperitoneal or subcutaneous route. The average reation time ofeach group is determined again at 30,60 and 90 minutes after compound administration and is compared to controls. Reaction time is recorded as percent changes from control. All groups are averaged before and after treatment. A combined reaction time average (recorded as percent change of reaction time threshold from controls) for all three periods is plotted against dose on graph paper, and a curve is drawn. The ED 50 is read from this curve.

When 6-chloro-l ,2,3 ,4-tetrahydrocarbazole-2- carboxylic acid, which has demonstrated an LD of, for example, 1120 mg. p.o. in mice, is utilized as the test substance at a dose ranging 'from 38 mg. to about 220 mg, analgesic activity is observed.

The compounds of formula I, their enantiometers and salts thereof as herein described, have effects qualitatively similar to those of phenylbutazone, known for its therapeutic uses and properties. Thus, the end products of this invention demonstrate a pattern of activity associated with anti-inllammatory agents ofknown efficacy and safety.

The compounds of formula l, their enantiomers and salts thereof as herein described, can be incorporated into standard pharmaceutical dosage forms, for example, they are useful for oral or parenteral application with the usual pharmaceutical adjuvant material, for example, organic or inorganic inert carrier materials such as water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, gums, polyalkyleneglycols, and the like. The pharmaceutical preparations can be employed in a solid form, for example, as tablets, troches, suppositories, capsules, or in liquid form, for example, as solutions, suspensions or emulsions. Pharmaceutical adjuvant materials can be added and include preservatives, stabilizers, wetting or emulsifying agents, salts to change the osmotic pressure or to act as buffers. The pharmaceutical preparations can also contain other therapeutically active substances.

Since the compounds of the invention possess asymmetric carbon atoms, they are ordinarily obtained as racemic mixtures. The resolution of such racemates into the optically active isomers can be carried out by known procedures. Some raceinic mixtures can be precipitated as eutectics and can thereafter be separated. Chemical resolution is, however, preferred. By this method, diastereomers are formed from the racemic mixture with an optically active resolving agent, for example, an optically active base, such as d-a-( l naphthyl)ethylamine, which can be reacted with the carboxyl group. The formed diastereomers are separated by selective crystallization and converted to the corresponding optical isomer. Thus, the invention covers the racemates of the compounds of formula I as well as their optically active isomers.

The following examples further illustrate the invention. All temperatures are in degrees centigrade, unless otherwise mentioned.

EXAMPLE 1 Preparation of 6-chloro-l ,2,3,4-tetrahydroearbazole-2-carboxylic acid A mixture of 50 g. of p-chlorophenylhydrazine hydrochloride (formula II), 500 ml. of percent acetic acid and 42 g. of cyclohexanone-3-carboxylic acid (formula III) was placed in a 1 liter round-bottomed, threenecked flask equipped with stirrer and reflux condenser. The mixture was stirred for 2 hours at room temperature under nitrogen and then heated to reflux. After stirring under reflux for 2.5 hours, the mixture was poured into a stirred mixture of 1 kg. of ice and 1 liter of water and stirred until the ice melted. Following filtration of the aqueous mixture, the filter cake was washed with water (4 X ml.). Following removal of as much water as possible by filtration, the filter cake was placed in a vacuum oven and dried for 12 hours at l20 over sodium hydroxide pellets in vacuo. The dried filter cake (66 g.) was dissolved in 500 ml. of boiling ethanol, filtered through a heated funnel, and the filtrate concentrated to 400 ml. under a nitrogen atmosphere. When the solution cooled to room temperature, the mixture was set in a refrigerator at 5C. for 72 hours to complete the crystallization. The crystalline product was collected by filtration and the filter cake was washed with cooled ethanol (2 X 30 ml.). There was obtained 40 g. (58 percent) of 6-chloro-1,2,3,4- tetrahydrocarbazole-2-carboxylic acid as a yellowishtan powder which melted at 249250 when dried in vacuo over P Concentration of the mother liquors in a Swisco under nitrogen to 150 ml. gave an additional 10.4 g. (m.p. 242246). This second crop melted at 247248 when recrystallized from 80 ml. of ethanol.

In an analogous manner to Example 1, when the phenylhydrazine of formula II was replaced, as hereinafter set forth, the corresponding 1,2,3,4-

tetrahydrocarbazole-Z-carboxylic acids were obtained:

EXAMPLE 2 Paramethylphenylhydrazine 6-methyl-1,2,3,4- tetrahydrocarbazole-Z-carboxylic acid, m.p. 254255 (EtOAc) EXAMPLE 3 Paramethoxyphenylhydrazine 6-methoxyl2,3,4-tclrahydrocarbazole-2-carboxylic acid, m.p. 22(1-227 (EtOAc) EXAMPLE 4 N 4-chlorobenzyl )-paramethoxyphenyl-hydrazine 9-(4-chlorobenzyl)-6-methoxy-1,2,3,4- tetrahydrocarbazole-Z-carboxylic acid, m.p. 211.5212(EtOAc) EXAMPLE 5 Paranitrophenylhydrazine 6-nitro-l ,2,3,4- tetrahydrocarbazole-Z-carboxylic acid, m.p. 263265 (EtOAc) EXAMPLE 6 Metachlorophenylhydrazine 7-chloro'l,2,3,4- tetrahydrocarbazole-Z-carboxylic acid, m.p. 238240 (EtOAc) EXAMPLE 7 Metamethylphenylhydrazine 7-methyl-1,2,3,4- tetrahydrocarbaz0le-2-carboxylic acid, m.p. 229-231 (EtOAc) EXAMPLE 8 Orthochlorophenylhydrazine 8-chloro-l,2,3,4- tetrahydrocarbazole-Z-carboxylic acid, m.p. 189-190 (benzene) tetrahydr0carbazole-2-carboxylic acid, m.p. 256-257 (EtOAc) EXAMPLE l0 Parabromophenylhydrazine 6-bromo-l ,2,3,4- tetrahydrocarbazole-Z-carboxylic acid, m.p. 229-230 (EtOAc) EXAMPLE ll 3,4-Dichlorophenylhydrazine 6,7-dichlorol,2,3,4-tetrahydrocarbazole-Z-carboxylic acid, m.p. BOW-3 10 (MeOH) EXAMPLE l2 3,4-Dichlorophenylhydrazine 5,6-dichlorol,2,3,4-tetrahydrocarbazole-2-earhoxylic acid, m.p. 229-23() (benzene) The compound of Example 11 was separated from the compound of Example 12 by fractional crystallization of ethanol solutions of the mixture obtained in the reaction.

EXAMPLE l3 Paratrifluoromethylphenylhydrazine 6- trifluoromethyl- 1 ,2,3 ,4-tetrahydrocarbazole-2- carboxylic acid, m.p. 233-234 (decomp.) (EtOAc) EXAMPLE l6 1-Methyl-l-phenylhydrazine 9-methyl- 1 ,2,3,4- tetrahydrocarbazole-Z-carboxylic acid, m.p. 228-229 (benzene) EXAMPLE l7 2,3-Dichlorophenylhydrazine 7,8-dichloro- 1,2,3,4-tetrahydrocarbazole-2-carboxylic acid, m.p. 217-218 (acetonitrile) EXAMPLE l8 Parasulfamidophenylhydrazine 1,2,3,4- tetrahydro-6-sulfamoylcarbazole-2-carboxylic acid, m.p. m.p. 293294 (water) EXAMPLE l9 Para-(difluoromethylsulfonyl)phenylhydrazine 6-difluoromethylsulfonyl-l ,2,3,4-tetrahydrocarbazole- 2-carboxylic acid, m.p. 235-236 (EtOAc) EXAMPLE 20 Paracarbethoxyphenylhydrazine-- 6-carbethoxy l,2,3,4-tetrahydrocarbazole-2-carboxylic acid, m.p.

222-223 (EtOAc) EXAMPLE 21 4-Aminosulfonyl-3-chlorophenylhydrazine 5- chloro-l ,2,3 ,4-tetrahydro-6-sulfoamylcarbazole-2- carboxylic acid, m.p. 296-298 (EtOH) EXAMPLE 22 Para-(dimethylsulfamoyl)phenylhydrazine 6- dimethylsulfamoyl-l ,2,3 ,4-tetrahydrocarbazole-2- carboxylic acid, m.p. 242243 (EtOH) EXAMPLE 23 Paramethylthiophenylhydrazine- 6-mcthylthi0- l,2,3,4-tetrahydrocarbazole-Z-carboxylic acid, m.p. 2l22l3 (EtOAc) EXAMPLE 24 Parabenzyloxyphenylhydrazine 6-benzyloxyl,2,3,4-tetrahydrocarbazole-Z-carboxylic acid, m.p. 225227 (EtOAc) EXAMPLE 25 Paracyanophenylhydrazine 6-cyano-1,2,3,4- tetrahydrocarbazole-Z-carboxylic acid, m.p. 302305 (iso PrOH) EXAMPLE 26 Paracarboxyphenylhydrazine 6-carboxyl ,2,3 ,4- tetrahydrocarbazole-Z-carboxylic acid, m.p. 327-329 (EtOH) EXAMPLE 27 Paraethylphenylhydrazine 6-ethyl-l ,2,3,4- tetrahydrocarbazole-2-carboxylic acid, m.p. 231232 (EtOAc) EXAMPLE 28 3,4-mcthylenedioxyphenylhydrazine 6,7- methylencdioxy-l ,2,3,4-tetrahydrocarbazole-Z- carboxylic acid, m.p. 265-267 (EtOAc) EXAMPLE 29 Paraacetylphenylhydrazine 6-acetyl-l,2,3,4- tetrahydrocarbazole-2-carboxylic acid, m.p. 295297 (EtOH) EXAMPLE 30 EXAMPLE 3] Cyclopentanone3-acetic acid 7-chlorocyclopcntalblindole-Z-acetic acid, m.p. l63164 (EtOAc). lts piperidino salt has a melting point of l59l60 EXAMPLE 32 Cyclopentanone-3-carboxylic acid 7-chlorocyclopenta[blindole-Z-carboxylic acid, m.p. 197l99 (EtOAc) EXAMPLE 33 Cyclopentanone-3-carboxylic acid ethyl ester- 7- chlorocyclopenta[b]indole-2-carboxylic acid ethyl ester EXAMPLE 34 Cyclohexanone-3-acetic acid 6-chloro-1,2,3,4- tetrahydrocarbazo]e-2-acetic acid, m.p. l84-l86 (benzene) EXAMPLE 35 3-cyclohexanone-a-methylacetic acid- 6-chloroa-mcthyll ,2,3,4-tetrahydrocarbazole-Z-acetic acid (cis-trans isomers), m.p. 2l5216 (EtOAc) EXAMPLE 36 Utilizing the procedure of Example 1, paramethylphenylhydrazine was reacted with cyclopentanone-3- carboxylic acid to give 7-methyl-1,2,3,4-tetrahydrocyclopenta[b]indole carboxylic acid, m.p. 250 (decomp).

EXAMPLE 37 Preparation of 9-benzoyl-6-chloro-1,2,3 ,4-tetrahydrocarbazole-2- carboxylic acid A stirred mixture of 2.0 g. of N-p-chlorophenyl-N- benzoylhydrazine, 1.1 g. of cyclohexanone-3- carboxylic acid, 5 ml. of glacial acetic acid and 7 ml. of cyclohexane were heated under an atmosphere of nitrogen. After 3 hours of stirring at reflux, the reaction mixture was concentrated under reduced pressure and 10 ml. of ethanol was added to the residue. After standing overnight in the refrigerator, the insoluble portion was removed by filtration, washed with a small amount of cold ethanol and dried, yielding 0.4 g. of product, m.p. l96197. Following a recrystallization from ethanol, 0.2 g. of 9-benzoyl-6-chloro-l ,2,3 ,4- tetrahydrocarbazole-2-carboxylic acid was obtained, m.p. 207-208.

EXAMPLE 38 An alternate preparation of (i) 6-chloro l ,2,3,4-tetrahydrocarbazole-2-carboxylic acid A stirred mixture of 100 mg. of 9-benzoyl-6-chlorol,2,3,4-tetrahydrocarbazole-2-carboxylic acid and 5 ml. of 3N sodium hydroxide was heated on a steam bath for 5 minutes and cooled to room temperature. After 1 hour at room temperature, the reaction mixture was further cooled in an ice bath, filtered and the filter cake was washed with 10 drops of cold water. The filter cake was dissolved in 20 ml. of warm water, and the re-' sulting warm solution was made strongly acid with 1N hydrochloric acid. Following filtration, washing with warm water and drying, 56 mg. of (i) 6-chloro-l ,2,3,4- tetrahydrocarbazole-2-carboxylic acid was obtained, m.p. 247249.

EXAMPLE 39 Preparation of 6-chloro-1 ,2,3,4-tetrahydrocarbazole-Z-carboxylic acid A solution of 8.8 g. (0.0515 mole) of l-a-(l-naphthyl)ethylamine in 50 ml. of acetone was carefully added to a warm solution of 12.7 g. (0.051 mole) of (i) 6-chlorol ,2,3,4-tetrahydrocarbazole-2-carboxylic acid. After standing at room temperature for 48 hours, the mixture was filtered and the filter cake was washed with cold acetone, yielding 11.7 g. of a colorless salt, m.p. 188-191; [0:1 2.4, which upon recrystallization from 100 ml. of acetone returned 4.8 g. of salt, m.p. 192-193; [(11 15.5. Upon two subsequent recrystallizations from acetone, 1.20 g., m.p. 196197; [01],, 31.1 was obtained. The salt (1.20

g g.) was dissolved in warm acetone and after filtration,

the solution was poured into a mixture of ice and hydrochloric acid. Following filtration and drying, 0.60 g. of product was obtained which gave, after crystallization from ethyl acetate, 0.45 g. of 6-chloro-l ,2,3,4-

tetrahydrocarbazole-2-carboxylic 249251; [01],, 59.7.

EXAMPLE 40 acid, m.p.

in ml. of acetone was carefully added to a solution 10 of 2.7 g. of partially resolved 6-chloro-l,2,3,4- tetrahydrocarbazole-2-carboxylic acid ([01],, -15.9, recovered from the filtrate of a previous resolution of the racemate). After standing for 3 days at room temperature, the mixture was filtered and the filter cake was washed with cold acetone, yielding 2.3 g., m.p. l91193; [a],, 17.2. Following two additional recrystallizations from acetone, 0.38 g. was obtained, m.p. l96197; [011 33.2. The salt (0.38 g.) was dissolved in warm acetone, and the resulting solution was poured onto a mixture of ice and hydrochloric acid. Following filtration and drying, 0.17 g. of product was obtained, which upon crystallization from ethyl acetate gavev 0.098 g. of 6-chloro-1,2,3,4- tetrahydrocarbazole-2-carboxylic acid, m.p. 249250; [04],, 63.0.

EXAMPLE 41 Preparation of 6-chloro-l ,2,3,4-tetrahydrocarbazole-2-carboxylic acid methyl ester A mixture of 2 g. of 6-chloro-1,2,3,4- tetrahydrocarbazole-2-carboxylic acid and 40 ml. of methanol was heated to boiling on a steam bath. The solution was removed from the steam bath and three drops of concentrated sulfuric acid was added. The reaction was allowed to stand for 18 hours at room temperature and then cooled further for 2 hours in an ice bath. Following filtration, the filter cake was washed with cold methanol and air dried yielding 1.9 g. of 6- chloro-l,2,3,4-tetrahydrocarbazole-2-carboxylic acid methyl ester, m.p. 175l76.

EXAMPLE 42 Preparation of 6-chloro-1 ,2,3,4-tetrahydrocarbazole-2-carboxylic acid ethyl ester A solution of 2.8 g. of 6-chloro-l,2,3,4- tetrahydrocarbazole-Z-carboxylic acid, 40 ml. of ethanol and 10 ml. of 7.5M ethanolic hydrogen chloride was allowed to remain at room temperature for 3 days. The solution was then concentrated to dryness under reduced pressure and the residue was partitioned between ether (200 ml.) and 3 percent sodium bicarbonate (200 ml.). The ether was separated and washed by extraction with water (2 X 100 and dried anddried over anhydrous sodium sulfate. Following filtration of the desiccant, the ether was evaporated and the residue (2.9 g.) was recrystallized from ethanol to yield 2.4 g. of 6-chloro-1,2,3,4-tetrahydrocarbazole-2-carboxylic acid ethyl ester, melting at 141l42.

EXAMPLE 43 Preparation of 6-amino-l ,2,3,4-tetrahydrocarbazole-2-carboxylic acid ethyl ester A mixture of 1.3 g. of 6-nitro-l,2,3,4-

tetrahydrocarbazole-Z-carboxylic acid ethyl ester, 0.5 teaspoonful of Raney nickel and 100 ml. of ethanol was shaken in a Parr hydrogenation apparatus under 3.7 atmospheres of hydrogen at room temperature. After 2 hours of shaking the uptake of hydrogen had stopped. The catalyst was removed by filtration and the filtrate was concentrated to dryness, yielding 1.2 g. of product. Following recrystallization from a mixture of hexane and ethyl acetate, a yield of 0.8 g. of 6-amino-l,2,3,4- tetrahydrocarbazole-2-carboxylic acid ethyl ester, m.p. 123124 was obtained.

EXAMPLE 44 Preparation of 9-acetyl-6-chloro-l ,2,3 ,4-tetrahydrocarbazole-2- carboxylic acid ethyl ester A solution of 1.5 g. of 6-chloro-l,2,3,4- tetrahydrocarbazole-2-carboxylic acid ethyl ester, 20 ml. of chloroform, 2 ml. of acetic anhydride and 1 drop of concentrated sulfuric acid was stirred under reflux. After 7 hours the reaction mixture was poured onto ice (100 g.). When the ice melted, the mixture was extracted with chloroform (2 X 100 ml.). The chloroform phase was extracted with 5 percent sodium bicarbonate (2 X 50 ml.) and then extracted with water (2 X 100 ml.).

Following drying of the chloroform solution over anhydrous sodium sulfate, the desiccant was removed by filtration and the chloroform evaporated under reduced pressure yielding 1.0 g. of product. Upon recrystallization from ethanol, 0.5 g. of 9-acetyl-6-chloro- 1,2,3,4-tetrahydrocarbazole-Z-carboxylic acid ethyl ester, m.p. 96 was obtained.

EXAMPLE 45 Preparation of 6-dimethylamino-1,2,3 ,4-tetrahydrocarbazole-2- carboxylic acid ethyl ester A mixture of 3 g. of 6-nitro-l,2,3,4- tetrahydrocarbazole-2-carboxylic acid ethyl ester, ml. of methanol, 2.1 g. of 37 percent aqueous formaldehyde and 0.5 teaspoonful of Raney nickel was shaken in a Parr hydrogenation apparatus under 3.7 atmospheres of hydrogen at room temperature. After 4 hours of shaking, the uptake of hydrogen had stopped. The catalyst was removed by filtration, and the filtrate was concentrated to dryness, yielding 2.8 g. of product. Recrystallization from ethyl acetate gave 1.7 g. of 6- dimethylamino-1,2,3 ,4-tetrahydrocarbazole-2- carboxylic acid ethyl ester, m.p. 100-101.

EXAMPLE 46 Preparation of 6-chloro-9-methyl- 1 ,2,3 ,4-tetrahydrocarbazole-2- carboxylic acid A mixture of 4.6 g. of 6-chloro-9-methyl-l,2,3,4- tetrahydrocarbazole-Z-carboxylic acid ethyl ester, 25 ml. of ethanol and 25 ml. of 3N sodium hydroxide was refluxed and stirred for 6 hours. Upon cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure. The residue was dissolved in water (300 ml.) and filtered. The filter cake was washed with water (4 X 50 ml.) and dried, yielding 4.2 g. of product, m.p. 259260. Upon recrystallization from ethyl acetate, 4.0. g. of 6-chloro-9-methyl- 1,2,3,4-tetrahydrocarbazole-2-carboxylic acid was obtained, m.p. 259260.

EXAMPLE 47 Preparation of 6-chloro-9-methyl-1,2,3,4-tetrahydrocarbazole-2- carboxylic acid ethyl ester A mixture of 1.3 g. of 55 percent sodium hydride in mineral oil, 8 g. of 6-chloro1,2,3 ,4- tetrahydrocarbazole-2-carboxylic acid ethyl ester and 50 ml. of dimethylformamide was stirred at room temperature. After 1.5 hours all the sodium hydride had reacted and a solution of 4.5 g. of methyl iodide in ml. of dimethylformamide was added. The mixture was stirred for 6 hours between 60-65C. Upon cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure and the residue was partitioned between ether (200 ml.) and water (200 ml.). The ether phase was separated and washed by extraction with water (2 X 100 ml.). After the ether solution had dried over sodium sulfate, the desiccant was removed by filtration and the ether evaporated, yielding 7.2 g. of product. Following crystallization from methanol, 4.6 g. of 6-chloro-9-methyl-l,2,3,4- tetrahydrocarbazole2-carboxylic acid ethyl ester was obtained, m.p. 126l27.

EXAMPLE 48 Preparation of 6-chloro-1,2,3,4-tetrahydrocarbazoIe-Z-methanol To a stirred mixture of 1.3 g. oflithium aluminum hydride in 90 ml. of dry ether (under an atmospheric dry nitrogen) was added 3 g. of powdered 6-chloro-l,2,3,4- tetrahydrocarbazole-Z-carboxylic acid ethyl ester. Following the addition, the mixture was stirred under reflux for 7 hours and then cooled (10) in an ice bath. 10 ml. of water was then added dropwise. The mixture was stirred one-half hour at room temperature and filtered. The filter cake was washed with ether (3 X 50 ml.) and the combined filtrate and washings were dried over anhydrous sodium sulfate. Following filtration of the desiccant and evaporation of the ether solution, 2.3 g. of residue was obtained. Crystallization from ethyl acetate gave 14 g. of 6-chloro-1,2,3,4-tetrahydrocarbazole-Z-methanol, m.p. 168169.

EXAMPLE 49 To a stirred solution of 5.5 g. of 6-chloro-l,2,3,4- tetrahydrocarbazole-2-carboxylic acid ethyl ester in 40 ml. ofdimcthylformamide was added 0.9 g. of54.5 percent sodium hydride in mineral oil. After the mixture had stirred 1 hour at room temperature, 3.5 g. of pchlorobenzoyl chloride in 10 ml. of dimethylformamide was added dropwise over the course of 10 minutes. The mixture was then stirred for 5 hours between 60-70 and then poured onto ice (500 g.). The mixture was extracted with ether (3 X 150 ml.) and the ether was in turn extracted with water (5 X 100 ml.). After drying the ether solution over sodium sulfate, the desiccant was removed by filtration and the ether was evaporated. Upon recrystallization of the residue with ethyl acetate, 3.8 g. of product was obtained, m.p. 129132. Following two further recrystallizations from methanol, a yield of 2.3 g. of 6-chloro-9-(pchlorobenzoyl)-1,2,3,4-tetrahydrocarbazole-2- carboxylic acid ethyl ester was obtained, m.p. 136137.

EXAMPLE 50 Preparation of 6-chloro-1,2,3 ,4-tetrahydrocarbazole-2-carboxylic acid amide A mixture of 2.5 g. of methyl-6-chloro-1,2,3,4- tetrahydrocarbazole-Z-carboxylate, 20 g. of liquid ammonia and 150 ml. of methanol was placed in a pressure bottle. The mixture was shaken at 60 for 40 hours (internal pressure 60 lb/in Upon cooling to room temperature, the mixture was concentrated to dryness yielding 2.1 g. of product. Following a crystallization from ethyl acetate, 0.8 g. of 6-chloro-1,2,3,4- tetrahydrocarbazole-2-carboxylic acid amide was obtained, m.p. 203204.

EXAMPLE 51 Preparation of the piperidine salt of 6-chloro-1,2,3,4-tetrahydrocarbazole-Z-carboxylic acid The procedure of Example 1 was repeated to the point of obtaining the dried filter cake which was dissolved in 700 ml. of warm acetone (45). The resulting solution was cooled to 20C. with an ice bath. A solution of 23 g. of piperidine in ml. of acetone was then added wtih constant stirring to the solution of the filter cake, keeping the temperature below 25. The precipitated piperidine salt was allowed to remain in the ice bath for two hours to complete the crystallization and then filtered. The filter cake was washed with chilled acetone (6 X 50 ml.) and air dried for 24 hours. There was obtained 91.6 g. (98 percent) of a colorless crystalline piperidine salt of 6-chloro-1,2,3,4- tetrahydrocarbazole-Z-carboxylic acid, melting at 197-205 after sintering at 194.

EXAMPLE 52 Preparation of 6-chloro-2-cyano-1,2,3,4-tetrahydrocarbazole A suspension of 5 g. of 6-chloro-l,2,3,4- tetrahydrocarbazole-2-carboxamide in 50 ml. of phosphorus oxychloride was cooled in an ice water bath. After the addition of 5 ml. of triethylamine, the reaction mixture was heated for 1 /2 hours on a steam bath. The reaction mixture was then evaporated to dryness, and the residue was partitioned between ml. of methylene chloride and 50 m1. of water. The aqueous phase was extracted twice with 50 ml. portions of methylene chloride. The combined organic extracts were evaporated to dryness, dried over sodium sulfate and filtered through 50 g. of alumina Woelm activity 11. Evaporation of the eluates to dryness gave 4.8 g. (98

percent) of 6-chloro-2-cyano- 1 ,2,3 ,4- tetrahydrocarbazole, m.p. 81182.

EXAMPLE 53 Preparation of 2-acetyl-6-chloro-1 ,2 ,3 ,4-tetrahydrocarbazo1e A solution of 1.0 g. of 6-chl0ro-2-cyano-1,2,3,4- tetrahydrocarbazole in 15 ml. of tetrahydrofuran was added dropwise to a cooled (10C.), stirred solution of 9.6 g. of methyl magnesium iodide in 20 ml. of ether.

1 9 The reaction mixture was refluxed and stirred under an atmosphere of dry nitrogen for 24 hours. Thereafter, it was cooled to C. in an'ice bath and 50 ml. of cold water was carefully added followed by 3 ml. of concentrated hydrochloric acid. The mixture was heated for 3 EXAMPLE 54 Preparation of o-chloro-l ,2,3,4-tetrahydrocarbazole-Z-carboxylic acid dimethylaminoethyl ester A solution of 3.0 g. of dimethylaminoethylchloride in ml. of dimethylformamide was added dropwise to a stirred solution of 6-chloro-l ,2,3 ,4- tetrahydrocarbazole-2-carboxylic acid sodium salt (made from 4 g. of 6-chloro-l,2,3,4- tetrahydrocarbazole-2-carboxylic acid, 0.71 g. of 54.5 percent sodium hydride dispersion in mineral oil and 40 ml. of dimethylformamide). After the addition, the stirred mixture was heated to 70C. and held at that temperature for 4 hours. Upon cooling to room temperature, the reaction mixture was poured into a mixture of ice and water and extracted with ether. The ether extracted was washed by extraction with water, separated, and dried over anhydrous sodium sulfate. Following filtration of the desiccant and evaporation of the ether, a yield of 5 g. was obtained. Crystallization from acetone gave 3.1 g. of 6-chloro-l,2,3,4- tetrahydrocarbazole-2-carboxylic acid dimethylaminoethyl ester, m.p. l23l24.

EXAMPLE 55 Preparation of 6,9-dimethyll ,2,3,4-tetrahydrocarbazole-2-carboxylic acid A solution of 6 of 6-methyl-l,2,3,4- tetrahydrocarbazole-Z-carboxylic acid ethyl ester in ml. of dimethylformamide was added to a stirred mixture of 1.1 g. of Nal-l (55 percent suspension in mineral oil) in 10 ml. of dimethylformamide. After the mixture had stirred for 1 hour at room temperature, a solution of4 g. of methyliodide in 10 ml. of dimethylformamide was added dropwise. Following the last addition, the reaction mixture was stirred and heated (40) for 7 hours. Upon cooling to room temperature, the reaction mixture was poured onto ice and the mixture extracted with ether. The ether solution was washed with water and dried over anhydrous sodium sulfate. Following filtration of the desiccant and evaporation of the ether, a yield of 6.3 g. was obtained. Crystallization from methanol yielded 1.2 g. of 6,9-dimethyl-1,2,3,4- tetrahydrocarbazole-2-carboxylic acid ethyl ester, m.p. 84-85, which was dissolved in 10 ml. of ethanol and 10 ml. 3N sodium hydroxide was added. The solution was refluxed and stirred for 4 hours and concentrated to dryness on an evaporator. The residue was dissolved in 300 ml. of warm water and filtered through a celite filter bed. The filtrate was made acid and the resulting precipitate was filtered and washed with water. After drying, a yield of 1.0 g. was obtained. Crystallization from ethyl acetate afforded 0.6 g. of 6,9-dimethyl- 1,2,3,4-tetrahydrocarbazole-2-carboxylic acid, m.p. 240242.

EXAMPLE 56 Preparation of 6-chloro-1,2,3,4-tetrahydrocarbazole-Z-carboxylic acid dimethylaminoethyl ester hydrochloride A slight excess of 7.5N alcoholic hydrogen chloride was added to a solution of 2.7 g. of 6-chloro-1,2,3,4- tetrahydrocarbazole-2-carboxylic acid dimethylaminoethyl ester in 15 ml. of ethanol. Ether was added until crystallization was induced and the resulting precipitate was filtered and washed with a mixture of ethanol and ether. Upon drying, 2.8 g. of the salt, 6-chlorol,2,3,4-tetrahydrocarbazole-Z-carboxylic acid dimethylaminoethyl ester hydrochloride, m.p. 20l203, was obtained.

EXAMPLE 57 Preparation of 6-chloro-N,N-dimethyl-l ,2,3 ,4-tetrahydrocarbazole-2- carboxamide Under an atmosphere of nitrogen, 10 g. of 6-chlorol,2,3,4-tetrahydrocarbazole-2-carboxylic acid dimethyl amine salt was stirred and heated (230-250) for 7 hours. When the reaction mixture had cooled to room temperature, it was partitioned between chloroform and dilute sodium hydroxide. The chloroform layer was separated and washed with water. After drying over anhydrous sodium sulfate, the desiccant was removed by filtration and the chloroform evaporated, yielding 4.2 g. Crystallization from ethyl acetate afforded 1.0 g. of 6-chloro-N,N-dimethyl-1,2,3,4- tetrahydrocarbazole-2-carboxamide, m.p. 176-l77.

. EXAMPLE 58 Preparation of 6-methyl-l ,2,3 ,4-tetrahydrocarbazole-2-carboxylic acid ethyl ester 6-Methyl-1,2,3,4-tetrahydrocarbazole-2-carboxylic acid (10 g.) was dissolved in 300 ml. of warm ethanol and 5 ml. of 7N alcoholic hydrogen chloride was added. The solution was thoroughly mixed and allowed to remain at room temperature for 2 days. After cooling in an ice bath for 5 hours, the mixture was filtered and washed with several volumes of ethanol. Upon drying, a yield of 7.3 g. of 6-methyl-1,2,3,4- tetrahydrocarbazole-Z-carboxylic acid ethyl ester, m.p. l 17-1 18, was obtained.

EXAMPLE 59 Preparation of 6-hydroxy-1 ,2,3 ,4-tetrahydrocarbazole-2-carboxylic acid A mixture of 3 g. of 6-benzyloxy-1,2,3,4- tetrahydrocarbazole-Z-carboxylic acid, m1. of ethanol, 0.5 g. of 10 percent palladium on carbon and 20 ml. of water was shaken under an atmosphere of hydrogen (56 p.s.i.) at room temperature. After 4 hours of shaking, the hydrogen uptake had stopped and the reduction was terminated. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure, yielding 2.8 g. Crystallization from E. V. Drew Company, 522 Fifth Avenue, New York, NY.

Procedure 1. The Wccobee M and the carnauba wax were melted in a suitable size glass lined container (stainless steel may also be used), mixed well and cooled to 45C.

2. o-chloro-l .2,3,4-tetrahydrocarbazole-Z-carboxylic acid, which had been reduced to a fine powder with no lumps, was added and stirred until completely and uniformly dispersed.

3. The mixture was poured into suppository molds to yield suppositories having an individual weight of 1.3 gms.

4. The suppositories were cooled and removed from molds. They were individually wrapped in wax paper for packaging. (Foil may also be used).

EXAMPLE 61 6-chloro-l ,2,3,4-tetrahydrocarbazole-2-carboxylic acid Tablet Formulation Per Tablet (t-L'lllUTU-l.ZJA"Cll'ZlhyLllOClH'lHlZOlc- Z-carboxylic acid 25.00 mg. Lactose, [LS l. 64.50 mg. ('oru Slarch 10.00 mg. Magnesium Slcurale 0.50 mg.

Procedure:

1. 6-chloro-l ,2,3,4-tetrahydrocarbazole-Z-carboxylic acid was mixed with the lactose, corn starch and magnesium stearate in a suitable mixer.

2. The mixture was further blended by passing through a Fitzpatrick Comminuting Machine fitted with a No. 1A screen with knives forward.

3. The mixed powders were slugged on a tablet compressing machine.

4. The slugs were comminuted to a suitable mesh size (No. 16 screen) and mixed well.

5. The tablets were compressed at a tablet weight of 100 mg. using tablet punches having a diameter of approximately one-fourth inch. (Tablets may be wither flat or hieonvex and may be scored if desired.) 1

EXAMPLE 62 6-chlorol ,2,3,4-tetrahydrocarbazole-Z-carboxylic acid Capsule Formulation Per Capsule 6-chloro-l ,2,3,4-tetrahydrocarbazole- Z-carboxylic acid 50 mg. Lactose, U.S.P. l25 mg. Corn Starch, USP. 30 mg. Talc, U.S.Pv 5 mg.

Total Weight 2l0 mg.

Procedure:

EXAMPLE 63 6-chloro-l ,2,3,4-tetrahydrocarbazole-2-carboxylic acid Parenteral Formulation Each l cc. ampul contains:

Per cc.:

6-chloro-l ,2.3,4-tetrahydrocarbazolel0.2 mg.

2-carboxylic acid (2% excess) Methyl Paraben, U.S.P. L8 mg. Propyl Paraben, USP. 0.2 mg. Sodium Hydroxide, UlS. q.s. ph 8.0 Water for Injection, U.S.P. q.s. ad I cc.

Procedure (For 10,000 cc.):

1. In a clean glass or glass-lined vessel, 8,000 cc. of Water for Injection were heated to C. It was then cooled to 5060C. and 18 gms. of methyl paraben and 2 gms. of propyl paraben were added and dissolved with stirring. The solution was then allowed to cool to room temperature.

2. The l02.0 gms. of o-chloro-l ,2,3,4-

tetrahydrocarbazole-2-carhoxylic acid were added under an atmosphere of nitrogen and stirred until completely dispersed.

3. The sodium hydroxide was added as a 10 percent solution until the pH was adjusted to 8.0 plus or minus 0.2, and the drug was completely dissolved.

4. Sufficient water for injection was then added to make a total volume of 10,000 cc.

5. This solution was then filtered through an 02 Selas candle, filled into suitable size ampuls, gassed with nitrogen and sealed. It was autoclaved at 10 lbs. PSI for 30 minutes.

We claim:

1. A compound of the formula (RIM U "l" at \N lo I wherein r is l or 2; R is halogen or lower alkyl of l to 7 carbon atoms; R is hydrogen or lower alkyl; and B is selected from the group consisting of hydroxy, lower alkoxy, amino-lower alkoxy, monolower alkylamino-lower alkoxy and di-lower alkylamino-lower alkoxy,

its enantiomers, or when B is hydroxy, salts thereof with pharmaceutically acceptable bases, and when B is amino-lower alkoxy, mono-lower alkylamino-lower alkoxy or di-lower alkylamino-lower alkoxy, addition salts thereof with pharmaceutically acceptable acids.

2. A compound of the formula wherein R is halogen or lower alkyl ofl to 7 carbon atoms; R is hydrogen or lower alkyl; and B is selected from the group consisting of hydroxy, lower alkoxy, amino-lower alkoxy, mono-lower alkylamino-lower alkoxy, and di-lower alkylaminolower alkoxy, its enantiomers, or when B is hydroxy, salts thereof with pharmaceutically acceptable bases, and when E is amino-lower alkoxy, mono-lower alkylamino-lower alkoxy or di-lower alkylamino-lower alkoxy, addition salts thereof with pharmaceutically acceptable acids.

3. A compound in accordance with claim 2, 6-chlorol,2.3,4-tetrahydrocarbazole-2-carboxylic acid di-lower alkylamino-lower alkyl ester or addition salts thereof with pharmaceutically acceptable acids.

4. A compound in accordance with claim 3, 6-chlorol.2.3,4-tetrahydrocarbazole-2-carboxylic acid dimethylaminoethyl ester.

24 5. A compound in accordance with claim 3, 6-chloro- 1,2,3,4-tetrahydrocarbazole-2-carboxylic acid dimethylaminoethyl ester hydrochloride.

6. A compound in accordance with claim 2, 6-chl0rol,2,3,4-tetrahydrocarbazole-2-carboxylic acid lower alkyl ester.

7. A compound in accordance with claim 6, 6-chlorol,2,3,4-tetrahydrocarbazole-Z-carboxylic acid ethyl ester.

8. A compound in accordance with claim 2, of the formula I \/-co OH wherein R is halogen or lower alkyl, its enantiomers or salts thereof with pharmaceutically acceptable bases.

9. A compound in accordance with claim 8, wherein R, is halogen.

10. A compound in accordance with claim 9, 6- chloro-l ,2,3,4-tetrahydrocarbazole-2-carboxylic acid:

11. A compound in accordance with claim 10, 6-chlorol ,2,3 ,4-tetrahydrocarbazole-Z-carboxylic acid.

12. A compound in accordance with claim 10, 6-chloro-1 ,2,3 ,4-tetrahydrocarbazole-2-carboxylic acid.

13. A compound in accordance with claim 8, wherein R is lower alkyl.

14. A compound in accordance with claim 13, 6- methyl-l,2,3,4-tetrahydrocarbazole-2-carboxylic acid.

15. The compound in accordance with claim 1, 6,7- dichloro-l ,2,3,4-tetrahydrocarbazole-Z-carboxylic acid. 

1. A COMPPUND OF THE FORMULA
 2. A compound of the formula
 3. A compound in accordance with claim 2, 6-chloro-1,2,3,4-tetrahydrocarbazole-2-carboxylic acid di-lower alkylamino-lower alkyl ester or addition salts thereof with pharmaceutically acceptable acids.
 4. A compound in accordance with claim 3, 6-chloro-1,2,3,4-tetrahydrocarbazole-2-carboxylic acid dimethylaminoethyl ester.
 5. A compound in aCcordance with claim 3, 6-chloro-1,2,3,4-tetrahydrocarbazole-2-carboxylic acid dimethylaminoethyl ester hydrochloride.
 6. A compound in accordance with claim 2, 6-chloro-1,2,3,4-tetrahydrocarbazole-2-carboxylic acid lower alkyl ester.
 7. A compound in accordance with claim 6, 6-chloro-1,2,3,4-tetrahydrocarbazole-2-carboxylic acid ethyl ester.
 8. A compound in accordance with claim 2, of the formula
 9. A compound in accordance with claim 8, wherein R''1 is halogen.
 10. A compound in accordance with claim 9, 6-chloro-1,2,3,4-tetrahydrocarbazole-2-carboxylic acid.
 11. A compound in accordance with claim 10, (+) 6-chloro-1,2,3, 4-tetrahydrocarbazole-2-carboxylic acid.
 12. A compound in accordance with claim 10, (-) 6-chloro-1,2,3, 4-tetrahydrocarbazole-2-carboxylic acid.
 13. A compound in accordance with claim 8, wherein R''1 is lower alkyl.
 14. A compound in accordance with claim 13, 6-methyl-1,2,3,4-tetrahydrocarbazole-2-carboxylic acid.
 15. The compound in accordance with claim 1, 6,7-dichloro-1,2,3, 4-tetrahydrocarbazole-2-carboxylic acid. 